Basic and translational research focused on mechanisms by which the heart maintains cardiac function and recovers after injury.

Research
Description

We are interested in how the adult heart maintains itself for the 3+ billion heartbeats it must deliver to carry us through life. We use molecular and cellular biological techniques to approach specific questions related to this theme. Our specific ideas and questions are motivated by a clinical interest in understanding the pathophysiology of and treating congestive heart failure.

One specific system under active investigation is the neuregulin/erbB signaling system. The growth factor neuregulin acts through receptor tyrosine kinases in the erbB family to modulate cell growth and survival in many tissues. We have been studying how this works in the heart. Our interest is motivated in part by the clinical observation that treating cancer victims with erbB2-targeted therapies promotes cardiac dysfunction, particularly in patients who have received concurrent anthracyclines. We are using isolated cardiac microvascular endothelial cells and myocytes in primary culture to dissect how this system works. Through a series of small and large animal studies, and most recently a clinical trial, we are part of a team examining whether recombinant neuregulin can be developed as a therapy for heart failure. In parallel, we are applying what we are learning to develop strategies to prevent cardiac injury (and promote repair) in situations such as anthracycline exposure, ischemia, and cardiac amyloidosis.

As part of the NHLBI funded U01 Progenitor Cell Biology Consortium we are working with the Hatzopoulos, Baldwin, and Hong laboratories to identify host factors that regulate myocardial regeneration. We have identified neuregulin as one of those factors that regulates biology of endothelial and myocardial progenitor cells. We are now looking at other factors that may be correctable at the systemic level in a way that optimizes myocardial and other organ function. These are being studied in cell, animal and human tissue studies. We anticipate applying what we learn to develop clinical trials in human heart failure.

Clinical
Research Description

We are examining how circulating levels of proteins known to play a role in cardiac growth and repair from basic research relate to clinical parameters such as risk of heart failure, cardiovascular function, and exercise capacity. We are doing this through collaborations with large epidemiological studies such as the Framingham Heart Study, as well as through specific clinical studies involving subjects with heart failure as well as normal volunteers. One goal in this work is to develop sets of parameters that will predict outcome in the setting of cardiac dysfunction.

A related area of interest is to develop strategies that can promote cardiac protection of cancer victims undergoing treatment with chemotherapy regimens that include anthracyclines and ErbB2-targeted therapies. An ongoing study in breast cancer patients is examining the potential of physical activity to prevent cardiovascular effects of cancer therapy.

We have been a part of a team of investigators examining the potential of recombinant neuregulin as a treatment for heart failure.